Regulatory Themes and Variations by the Stress-Signaling Nucleotide Alarmones (p)ppGpp in Bacteria

Literature Cited

1. 1. 

   Ababneh QO, Herman JK. 2015. RelA inhibits Bacillus subtilis motility and chaining. J. Bacteriol. 197:128–37
   [Google Scholar]
2. 2. 

   Ahmad S, Wang B, Walker MD, Tran HR, Stogios PJ et al. 2019. An interbacterial toxin inhibits target cell growth by synthesizing (p)ppApp. Nature 575:674–78
   [Google Scholar]
3. 3. 

   Anderson BW, Hao A, Satyshur KA, Keck JL, Wang JD. 2020. Molecular mechanism of regulation of the purine salvage enzyme XPRT by the alarmones pppGpp, ppGpp, and pGpp. J. Mol. Biol. 432:4108–26
   [Google Scholar]
4. 4. 

   Anderson BW, Liu K, Wolak C, Dubiel K, She F et al. 2019. Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction. eLife 8:e47534
   [Google Scholar]
5. 5. 

   Anderson BW, Schumacher MA, Yang J, Turdiev A, Turdiev H et al. 2020. The nucleotide messenger (p)ppGpp is a co-repressor of the purine synthesis transcription regulator PurR in Firmicutes. bioRxiv 2020.12.02.409011. https://doi.org/10.1101/2020.12.02.409011
   [Crossref]
6. 6. 

   Arent S, Kadziola A, Larsen S, Neuhard J, Jensen KF. 2006. The extraordinary specificity of xanthine phosphoribosyltransferase from Bacillus subtilis elucidated by reaction kinetics, ligand binding, and crystallography. Biochemistry 45:6615–27
   [Google Scholar]
7. 7. 

   Atkinson GC, Tenson T, Hauryliuk V. 2011. The RelA/SpoT Homolog (RSH) superfamily: Distribution and functional evolution of ppGpp synthetases and hydrolases across the tree of life. PLOS ONE 6:e23479
   [Google Scholar]
8. 8. 

   Bennison DJ, Irving SE, Corrigan RM. 2019. The impact of the stringent response on TRAFAC GTPases and prokaryotic ribosome assembly. Cells 8:1313
   [Google Scholar]
9. 9. 

   Blumenthal T, Landers TA, Weber K. 1972. Bacteriophage Qβ replicase contains the protein biosynthesis elongation factors EF Tu and EF Ts. PNAS 69:1313–17
   [Google Scholar]
10. 10. 

    Britton RA. 2009. Role of GTPases in bacterial ribosome assembly. Annu. Rev. Microbiol. 63:155–76
    [Google Scholar]
11. 11. 

    Bruhn-Olszewska B, Molodtsov V, Sobala M, Dylewski M, Murakami KS et al. 2018. Structure-function comparisons of (p)ppApp vs (p)ppGpp for Escherichiacoli RNA polymerase binding sites and for rrnB P1 promoter regulatory responses in vitro. Biochim. Biophys. Acta Gene Regul. Mech. 1861:731–42
    [Google Scholar]
12. 12. 

    Buglino J, Shen V, Hakimian P, Lima CD. 2002. Structural and biochemical analysis of the Obg GTP binding protein. Structure 10:1581–92
    [Google Scholar]
13. 13. 

    Cashel M, Gallant J. 1969. Two compounds implicated in the function of the RC gene in Escherichia coli. Nature 221:838–41
    [Google Scholar]
14. 14. 

    Charity JC, Blalock LT, Costante-Hamm MM, Kasper DL, Dove SL. 2009. Small molecule control of virulence gene expression in Francisella tularensis. PLOS Pathog 5:e1000641
    [Google Scholar]
15. 15. 

    Colomer-Winter C, Flores-Mireles AL, Kundra S, Hultgren SJ, Lemos JA. 2019. (p)ppGpp and CodY promote Enterococcus faecalis virulence in a murine model of catheter-associated urinary tract infection. mSphere 4:e00392-19
    [Google Scholar]
16. 16. 

    Corrigan RM, Bellows LE, Wood A, Gründling A. 2016. ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria. PNAS 113:E1710–19
    [Google Scholar]
17. 17. 

    Corrigan RM, Bowman L, Willis AR, Kaever V, Gründling A. 2015. Cross-talk between two nucleotide-signaling pathways in Staphylococcus aureus. J. Biol. Chem. 290:5826–39
    [Google Scholar]
18. 18. 

    Cuthbert BJ, Ross W, Rohlfing AE, Dove SL, Gourse RL et al. 2017. Dissection of the molecular circuitry controlling virulence in Francisella tularensis. Genes Dev 31:1549–60
    [Google Scholar]
19. 19. 

    Dalebroux ZD, Svensson SL, Gaynor EC, Swanson MS 2010. ppGpp conjures bacterial virulence. Microbiol. Mol. Biol. Rev. 74:171–99
    [Google Scholar]
20. 20. 

    Das B, Bhadra RK. 2020. (p)ppGpp metabolism and antimicrobial resistance in bacterial pathogens. Front. Microbiol. 11:563944
    [Google Scholar]
21. 21. 

    deLivron MA, Robinson VL. 2008. Salmonella enterica serovar Typhimurium BipA exhibits two distinct ribosome binding modes. J. Bacteriol. 190:5944–52
    [Google Scholar]
22. 22. 

    Dey S, Pal A, Chakrabarti P, Janin J. 2010. The subunit interfaces of weakly associated homodimeric proteins. J. Mol. Biol. 398:146–60
    [Google Scholar]
23. 23. 

    Diez S, Ryu J, Caban K, Gonzalez RL Jr., Dworkin J. 2020. The alarmones (p)ppGpp directly regulate translation initiation during entry into quiescence. PNAS 117:15565–72
    [Google Scholar]
24. 24. 

    Echave J, Spielman SJ, Wilke CO. 2016. Causes of evolutionary rate variation among protein sites. Nat. Rev. Genet. 17:109–21
    [Google Scholar]
25. 25. 

    Fan H, Hahm J, Diggs S, Perry JJP, Blaha G. 2015. Structural and functional analysis of BipA, a regulator of virulence in enteropathogenic Escherichia coli. J. Biol. Chem. 290:20856–64
    [Google Scholar]
26. 26. 

    Fernandez-Coll L, Cashel M. 2020. Possible roles for basal levels of (p)ppGpp: growth efficiency versus surviving stress. Front. Microbiol. 11:592718
    [Google Scholar]
27. 27. 

    Fung DK, Barra JT, Schroeder JW, Ying D, Wang JD 2020. A shared alarmone-GTP switch underlies triggered and spontaneous persistence. bioRxiv 2020.03.22.002139. https://doi.org/10.1101/2020.03.22.002139
    [Crossref]
28. 28. 

    Fung DK, Yang J, Stevenson DM, Amador-Noguez D, Wang JD. 2020. Small alarmone synthetase SasA expression leads to concomitant accumulation of pGpp, ppApp, and AppppA in Bacillus subtilis. Front. Microbiol. 11:2083
    [Google Scholar]
29. 29. 

    Gaca AO, Kajfasz JK, Miller JH, Liu K, Wang JD et al. 2013. Basal levels of (p)ppGpp in Enterococcus faecalis: the magic beyond the stringent response. mBio 4:e00646-13
    [Google Scholar]
30. 30. 

    Gaca AO, Kudrin P, Colomer-Winter C, Beljantseva J, Liu K et al. 2015. From (p)ppGpp to (pp)pGpp: characterization of regulatory effects of pGpp synthesized by the small alarmone synthetase of Enterococcus faecalis. J. Bacteriol. 197:2908–19
    [Google Scholar]
31. 31. 

    Ge X, Cai Y, Chen Z, Gao S, Geng X et al. 2018. Bifunctional enzyme SpoT is involved in biofilm formation of Helicobacter pylori with multidrug resistance by upregulating efflux pump Hp1174 (gluP). Antimicrob. Agents Chemother. 62:e00957-18
    [Google Scholar]
32. 32. 

    Gourse RL, Chen AY, Gopalkrishnan S, Sanchez-Vazquez P, Myers A, Ross W. 2018. Transcriptional responses to ppGpp and DksA. Annu. Rev. Microbiol. 72:163–84
    [Google Scholar]
33. 33. 

    Hamel E, Cashel M. 1974. Guanine nucleotides in protein synthesis: utilization of pppGpp and dGTP by initiation factor 2 and elongation factor Tu. Arch. Biochem. Biophys. 162:293–300
    [Google Scholar]
34. 34. 

    Hauryliuk V, Atkinson GC, Murakami KS, Tenson T, Gerdes K. 2015. Recent functional insights into the role of (p)ppGpp in bacterial physiology. Nat. Rev. Microbiol. 13:298–309
    [Google Scholar]
35. 35. 

    Hengge R. 2020. Linking bacterial growth, survival, and multicellularity—small signaling molecules as triggers and drivers. Curr. Opin. Microbiol. 55:57–66
    [Google Scholar]
36. 36. 

    Hesketh A, Vergnano M, Wan C, Oliver SG. 2017. Bacterial signaling nucleotides inhibit yeast cell growth by impacting mitochondrial and other specifically eukaryotic functions. mBio 8:e01047-17
    [Google Scholar]
37. 37. 

    Huynh TN, Luo S, Pensinger D, Sauer J-D, Tong L, Woodward JJ. 2015. An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. PNAS 112:E747–56
    [Google Scholar]
38. 38. 

    Irving SE, Choudhury NR, Corrigan RM. 2020. The stringent response and physiological roles of (pp)pGpp in bacteria. Nat. Rev. Microbiol. 19:256–71
    [Google Scholar]
39. 39. 

    Ito D, Kawamura H, Oikawa A, Ihara Y, Shibata T et al. 2020. ppGpp functions as an alarmone in metazoa. Commun. Biol. 3:671
    [Google Scholar]
40. 40. 

    Jenal U, Reinders A, Lori C. 2017. Cyclic di-GMP: second messenger extraordinaire. Nat. Rev. Microbiol. 15:271–84
    [Google Scholar]
41. 41. 

    Jimmy S, Saha CK, Kurata T, Stavropoulos C, Oliveira SRA et al. 2020. A widespread toxin–antitoxin system exploiting growth control via alarmone signaling. PNAS 117:10500–10
    [Google Scholar]
42. 42. 

    Kanjee U, Gutsche I, Alexopoulos E, Zhao B, El Bakkouri M et al. 2011. Linkage between the bacterial acid stress and stringent responses: the structure of the inducible lysine decarboxylase. EMBO J 30:931–44
    [Google Scholar]
43. 43. 

    Kanjee U, Ogata K, Houry WA. 2012. Direct binding targets of the stringent response alarmone (p)ppGpp. Mol. Microbiol. 85:1029–43
    [Google Scholar]
44. 44. 

    Kihira K, Shimizu Y, Shomura Y, Shibata N, Kitamura M et al. 2012. Crystal structure analysis of the translation factor RF3 (release factor 3). FEBS Lett 586:3705–9
    [Google Scholar]
45. 45. 

    Krásný L, Tišerová H, Jonák J, Rejman D, Šanderová H. 2008. The identity of the transcription +1 position is crucial for changes in gene expression in response to amino acid starvation in Bacillus subtilis. Mol. Microbiol. 69:42–54
    [Google Scholar]
46. 46. 

    Kriel A, Brinsmade SR, Tse JL, Tehranchi AK, Bittner AN et al. 2014. GTP dysregulation in Bacillus subtilis cells lacking (p)ppGpp results in phenotypic amino acid auxotrophy and failure to adapt to nutrient downshift and regulate biosynthesis genes. J. Bacteriol. 196:189–201
    [Google Scholar]
47. 47. 

    Krüger L, Herzberg C, Wicke D, Bähre H, Heidemann JL et al. 2020. A rendezvous of two second messengers: The c-di-AMP receptor protein DarB controls (p)ppGpp synthesis in Bacillus subtilis. bioRxiv 2020.08.27.268672. https://doi.org/10.1101/2020.08.27.268672
    [Crossref]
48. 48. 

    Kudrin P, Dzhygyr I, Ishiguro K, Beljantseva J, Maksimova E et al. 2018. The ribosomal A-site finger is crucial for binding and activation of the stringent factor RelA. Nucleic Acids Res 46:1973–83
    [Google Scholar]
49. 49. 

    Kundra S, Colomer-Winter C, Lemos JA. 2020. Survival of the fittest: the relationship of (p)ppGpp with bacterial virulence. Front. Microbiol. 11:601417
    [Google Scholar]
50. 50. 

    Kushwaha GS, Patra A, Bhavesh NS. 2020. Structural analysis of (p)ppGpp reveals its versatile binding pattern for diverse types of target proteins. Front. Microbiol. 11:575041
    [Google Scholar]
51. 51. 

    Legault L, Jeantet C, Gros F. 1972. Inhibition of in vitro protein synthesis by ppGpp. FEBS Lett 27:71–75
    [Google Scholar]
52. 52. 

    Liu K, Myers AR, Pisithkul T, Claas KR, Satyshur KA et al. 2015. Molecular mechanism and evolution of guanylate kinase regulation by (p)ppGpp. Mol. Cell 57:735–49
    [Google Scholar]
53. 53. 

    Lopez JM, Marks CL, Freese E. 1979. The decrease of guanine nucleotides initiates sporulation of Bacillus subtilis. Biochim. Biophys. Acta Gen. Subj. 587:238–52
    [Google Scholar]
54. 54. 

    Mak KH, Zhao Q, Hu P-W, Au-Yeung C-L, Yang J et al. 2020. Lysosomal nucleotide metabolism regulates ER proteostasis through mTOR signaling. bioRxiv 2020.04.18.048561. https://doi.org/10.1101/2020.04.18.048561
    [Crossref]
55. 55. 

    Miller DL, Cashel M, Weissbach H. 1973. The interaction of guanosine 5′-diphosphate, 2′ (3′)-diphosphate with the bacterial elongation factor Tu. Arch. Biochem. Biophys. 154:675–82
    [Google Scholar]
56. 56. 

    Mirouze N, Prepiak P, Dubnau D. 2011. Fluctuations in spo0A transcription control rare developmental transitions in Bacillus subtilis. PLOS Genet 7:e1002048
    [Google Scholar]
57. 57. 

    Mitkevich VA, Ermakov A, Kulikova AA, Tankov S, Shyp V et al. 2010. Thermodynamic characterization of ppGpp binding to EF-G or IF2 and of initiator tRNA binding to free IF2 in the presence of GDP, GTP, or ppGpp. J. Mol. Biol. 402:838–46
    [Google Scholar]
58. 58. 

    Molodtsov V, Sineva E, Zhang L, Huang X, Cashel M et al. 2018. Allosteric effector ppGpp potentiates the inhibition of transcript initiation by DksA. Mol. Cell 69:828–39.E5
    [Google Scholar]
59. 59. 

    Najmanovich RJ. 2017. Evolutionary studies of ligand binding sites in proteins. Curr. Opin. Struct. Biol. 45:85–90
    [Google Scholar]
60. 60. 

    Nishino T, Gallant J, Shalit P, Palmer L, Wehr T. 1979. Regulatory nucleotides involved in the Rel function of Bacillus subtilis. J. Bacteriol. 140:671–79
    [Google Scholar]
61. 61. 

    Ooga T, Ohashi Y, Kuramitsu S, Koyama Y, Tomita M et al. 2009. Degradation of ppGpp by Nudix pyrophosphatase modulates the transition of growth phase in the bacterium Thermus thermophilus. J. Biol. Chem. 284:15549–56
    [Google Scholar]
62. 62. 

    Pacios O, Blasco L, Bleriot I, Fernandez-Garcia L, Ambroa A et al. 2020. (p)ppGpp and its role in bacterial persistence: new challenges. Antimicrob. Agents Chemother 64:e01283-20
    [Google Scholar]
63. 63. 

    Pausch P, Steinchen W, Wieland M, Klaus T, Freibert SA et al. 2018. Structural basis for (p)ppGpp-mediated inhibition of the GTPase RbgA. J. Biol. Chem. 293:19699–709
    [Google Scholar]
64. 64. 

    Petchiappan A, Naik SY, Chatterji D. 2020. RelZ-mediated stress response in Mycobacterium smegmatis: pGpp synthesis and its regulation. J. Bacteriol. 202:e00444-19
    [Google Scholar]
65. 65. 

    Peterson BN, Young MKM, Luo S, Wang J, Whiteley AT et al. 2020. (p)ppGpp and c-di-AMP homeostasis is controlled by CbpB in Listeria monocytogenes. mBio 11:e01625-20
    [Google Scholar]
66. 66. 

    Potrykus K, Cashel M. 2008. (p)ppGpp: still magical?. Annu. Rev. Microbiol. 62:35–51
    [Google Scholar]
67. 67. 

    Puszynska AM, O'Shea EK 2017. ppGpp controls global gene expression in light and in darkness in S. elongatus. Cell Rep 21:3155–65
    [Google Scholar]
68. 68. 

    Rhaese HJ, Hoch JA, Groscurth R. 1977. Studies on the control of development: isolation of Bacillus subtilis mutants blocked early in sporulation and defective in synthesis of highly phosphorylated nucleotides. PNAS 74:1125–29
    [Google Scholar]
69. 69. 

    Rojas AM, Ehrenberg M, Andersson SGE, Kurland CG. 1984. ppGpp inhibition of elongation factors Tu, G and Ts during polypeptide synthesis. Mol. Gen. Genet. 197:36–45
    [Google Scholar]
70. 70. 

    Ronneau S, Hallez R. 2019. Make and break the alarmone: regulation of (p)ppGpp synthetase/hydrolase enzymes in bacteria. FEMS Microbiol. Rev. 43:389–400
    [Google Scholar]
71. 71. 

    Ross W, Sanchez-Vazquez P, Chen AY, Lee J-H, Burgos HL, Gourse RL. 2016. ppGpp binding to a site at the RNAP-DksA interface accounts for its dramatic effects on transcription initiation during the stringent response. Mol. Cell 62:811–23
    [Google Scholar]
72. 72. 

    Rymer RU, Solorio FA, Tehranchi AK, Chu C, Corn JE et al. 2012. Binding mechanism of metal⋅NTP substrates and stringent-response alarmones to bacterial DnaG-type primases. Structure 20:1478–89
    [Google Scholar]
73. 73. 

    Sanchez-Vazquez P, Dewey CN, Kitten N, Ross W, Gourse RL. 2019. Genome-wide effects on Escherichia coli transcription from ppGpp binding to its two sites on RNA polymerase. PNAS 116:8310–19
    [Google Scholar]
74. 74. 

    Saraste M, Sibbald PR, Wittinghofer A. 1990. The P-loop–a common motif in ATP- and GTP-binding proteins. Trends Biochem. Sci. 15:430–34
    [Google Scholar]
75. 75. 

    Sherlock ME, Sudarsan N, Breaker RR. 2018. Riboswitches for the alarmone ppGpp expand the collection of RNA-based signaling systems. PNAS 115:6052–57
    [Google Scholar]
76. 76. 

    Shyp V, Dubey BN, Böhm R, Hartl J, Nesper J et al. 2021. Reciprocal growth control by competitive binding of nucleotide second messengers to a metabolic switch in Caulobacter crescentus. Nat. Microbiol. 6:59–72
    [Google Scholar]
77. 77. 

    Shyp V, Tankov S, Ermakov A, Kudrin P, English BP et al. 2012. Positive allosteric feedback regulation of the stringent response enzyme RelA by its product. EMBO Rep 13:835–39
    [Google Scholar]
78. 78. 

    Sinha SC, Krahn J, Shin BS, Tomchick DR, Zalkin H, Smith JL. 2003. The purine repressor of Bacillus subtilis: a novel combination of domains adapted for transcription regulation. J. Bacteriol. 185:4087–98
    [Google Scholar]
79. 79. 

    Sinha SC, Smith JL. 2001. The PRT protein family. Curr. Opin. Struct. Biol. 11:733–39
    [Google Scholar]
80. 80. 

    Sobala M, Bruhn-Olszewska B, Cashel M, Potrykus K. 2019. Methylobacterium extorquens RSH enzyme synthesizes (p)ppGpp and pppApp in vitro and in vivo, and leads to discovery of pppApp synthesis in Escherichia coli. Front. Microbiol. 10:859
    [Google Scholar]
81. 81. 

    Sonenshein AL. 2000. Control of sporulation initiation in Bacillus subtilis. Curr. Opin. Microbiol. 3:561–66
    [Google Scholar]
82. 82. 

    Sonenshein AL. 2007. Control of key metabolic intersections in Bacillus subtilis. Nat. Rev. Microbiol. 5:917–27
    [Google Scholar]
83. 83. 

    Steinchen W, Bange G. 2016. The magic dance of the alarmones (p)ppGpp. Mol. Microbiol. 101:531–44
    [Google Scholar]
84. 84. 

    Steinchen W, Schuhmacher JS, Altegoer F, Fage CD, Srinivasan V et al. 2015. Catalytic mechanism and allosteric regulation of an oligomeric (p)ppGpp synthetase by an alarmone. PNAS 112:13348–53
    [Google Scholar]
85. 85. 

    Steinchen W, Zegarra V, Bange G. 2020. (p)ppGpp: magic modulators of bacterial physiology and metabolism. Front. Microbiol. 11: 2072.
    [Google Scholar]
86. 86. 

    Stulke J, Kruger L. 2020. Cyclic di-AMP signaling in bacteria. Annu. Rev. Microbiol. 74:159–79
    [Google Scholar]
87. 87. 

    Sugliani M, Abdelkefi H, Ke H, Bouveret E, Robaglia C et al. 2016. An ancient bacterial signaling pathway regulates chloroplast function to influence growth and development in Arabidopsis. Plant Cell 28:661–79
    [Google Scholar]
88. 88. 

    Sun D, Lee G, Lee JH, Kim H-Y, Rhee H-W et al. 2010. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nat. Struct. Mol. Biol. 17:1188–94
    [Google Scholar]
89. 89. 

    Vadia S, Tse JL, Lucena R, Yang Z, Kellogg DR et al. 2017. Fatty acid availability sets cell envelope capacity and dictates microbial cell size. Curr. Biol. 27:1757–67.e5
    [Google Scholar]
90. 90. 

    Wang B, Dai P, Ding D, Del Rosario A, Grant RA et al. 2019. Affinity-based capture and identification of protein effectors of the growth regulator ppGpp. Nat. Chem. Biol. 15:141–50
    [Google Scholar]
91. 91. 

    Wang B, Grant RA, Laub MT. 2020. ppGpp coordinates nucleotide and amino-acid synthesis in E. coli during starvation. Mol. Cell 80:29–42.e10
    [Google Scholar]
92. 92. 

    Wang JD, Sanders GM, Grossman AD. 2007. Nutritional control of elongation of DNA replication by (p)ppGpp. Cell 128:865–75
    [Google Scholar]
93. 93. 

    Yamaguchi T, Iida K-I, Shiota S, Nakayama H, Yoshida S-I. 2015. Elevated guanosine 5′-diphosphate 3′-diphosphate level inhibits bacterial growth and interferes with FtsZ assembly. FEMS Microbiol. Lett. 362:fnv187
    [Google Scholar]
94. 94. 

    Yang J, Anderson BW, Turdiev A, Turdiev H, Stevenson DM et al. 2020. The nucleotide pGpp acts as a third alarmone in Bacillus, with functions distinct from those of (p)ppGpp. Nat. Commun. 11:5388
    [Google Scholar]
95. 95. 

    Zhang YE, Bærentsen RL, Fuhrer T, Sauer U, Gerdes K, Brodersen DE. 2019. (p)ppGpp regulates a bacterial nucleosidase by an allosteric two-domain switch. Mol. Cell 74:1239–49.e4
    [Google Scholar]
96. 96. 

    Zhang YE, Zborníková E, Rejman D, Gerdes K. 2018. Novel (p)ppGpp binding and metabolizing proteins of Escherichia coli. mBio 9:e02188-17
    [Google Scholar]